RESUMEN
N-Nitrosodimethylamine (NDMA) has been detected in some drug substances and pharmaceutical products containing sartans, ranitidine and metformin, and a potential risk of NDMA contamination exists in other drug substances and their pharmaceutical products. To quantitate NDMA in various drugs having diverse physicochemical properties, a specific, sensitive, and reliable analytical method is required, in addition to methods that can be applied to a class of nitrosamines. We aimed to develop an off-line isolation method for NDMA in drug substances using SPE for quantification with LC-APCI-MS/MS. Impediments to accurate quantitation of NDMA in drug substances using LC-MS/MS and insufficient durability of the system are attributed to the extremely large amounts of active pharmaceutical ingredients (APIs) in sample solutions in comparison to the trace amount of NDMA. A reduced retention of NDMA and/or decreased separation from other substances in LC, matrix effect in MS detection, and undesirable contamination of instruments with API and other substances may be occasionally encountered, all of which consequently result in deterioration of system performance and generation of unreliable data, even in the cases where a divert valve is configured between the column and ion source of the MS instrument. To address these problems, an off-line NDMA isolation methodology from APIs exhibiting diverse physicochemical properties, namely ranitidine hydrochloride (ranitidine), metformin hydrochloride (metformin), nizatidine, valsartan, and telmisartan, was developed. The applicability of the method was confirmed by batch analysis of metformin and ranitidine. Furthermore, contrary to previous reports, NDMA was found to be stable over a wide pH range. The proposed methodology and data from this study would contribute to the control of NDMA contamination in various drugs to realize the safe delivery of pharmaceuticals to patients.
Asunto(s)
Dimetilnitrosamina , Preparaciones Farmacéuticas , Cromatografía Liquida , Dimetilnitrosamina/análisis , Cromatografía de Gases y Espectrometría de Masas , Humanos , Extracción en Fase Sólida , Espectrometría de Masas en TándemRESUMEN
PURPOSE: Undesired drug sorption on laboratory material surfaces reduces the performance of analytical methods and results in the generation of unreliable data. Hence, we characterized the sorption of drugs and evaluated the sorption extent using a linear free energy relationship (LFER) model with Abraham solvation parameters of drugs. Furthermore, to prevent sorption, the effects of additives, such as organic solvents and salts, were evaluated. METHODS: The sorption of fifteen model drugs (concentration: 2 µM), with various physicochemical properties, on materials in 0.2% dimethyl sulfoxide aqueous solutions was evaluated. Drug sorption extent on the materials was determined using high-performance liquid chromatography. The obtained results were analyzed using an LFER model with Abraham solvation parameters of the drugs. The effect of additives on the sorption of itraconazole, one of the most hydrophobic drugs among those tested in this study, was investigated. RESULTS: Sorption was dependent on the physicochemical properties of drugs, rather than the type of materials used, and additives altered the rate of drug sorption. Equations were developed to evaluate the sorption extent (nmol) of drugs to glass and polypropylene using the Abraham solvation parameters of the drugs. CONCLUSIONS: LFER modeling with Abraham solvation parameters of drugs enabled us to evaluate drug sorption on materials. All the additives altered the rate of drug sorption, and some organic solvents effectively prevented sorption. The developed LFER model would be useful for assessment of the sorption properties of compounds in in vitro evaluations in drug discovery research and various other biochemical fields.